At our annual Innovator's retreat, our 2010 NYSCF -- Robertson Stem Cell Investigators Paul Tesar, PhD, of Case Western University, and Marius Wernig, MD, PhD, of Stanford University, discovered that they were working on the same topic, the direct conversion of skin cells into myelin-producing cells, called oligodendrocytes. That conversation led to the back-to-back publication of two studies in Nature Biotechnology. We spoke with Marius and Paul on how they worked together to publish this exciting discovery that could inform the treatment of multiple sclerosis and other myelin disorders.
Why did you focus on oligodendrocytes?
Paul Tesar: Myelin is produced by a cell type in the brain called the oligodendrocyte. With that myelin you have very severe disorders—the largest and most well-known is multiple sclerosis. When you lack this myelin sheath or when these oligodendrocytes are dysfunctional, you have a failure of the ability to communicate signals around those neurons or through those wires. Myelin damage can result in quite severe diseases.
Marius Wernig: We are very excited about oligodendrocytes—or more precisely their precursor cells, the oligodendrocyte precursor cell—because I personally think, and I don’t think I’m alone in that opinion in the field, that these cells are good candidates for a transplantation-based therapy. There are a lot of myelin diseases, or diseases that affect the myelin either directly or indirectly. For example, the best-known disease is MS, multiple sclerosis. There are a bunch of other myelin diseases, genetic forms, which tend to be rarer, but serve as a great proof of principal that such cell transplantation-based therapy actually can work.
Where do you see this work going in the future?
PT: Both our study and Marius’s study are with rodent cells, so we must caution at some level to not extend the results too far at this point, and our goal, of course, is to translate all of this work into human cells. The main focus in the stem cell field is on cell-, patient-specific therapy. I think in the shorter term, the cells we have created, these induced oligodendrocyte cells provide a means to rapidly create populations of oligodendrocyte lineage cells that we could use in the laboratory for drug-screening purposes or to understand diseases.
MW: Pelizaeus-Merzbacher disease, is probably the disease that we would attack first. This is the best-studied disease, best characterized. When we come in with the possibility, we have to, everything has to be taken with a grain of salt. Unfortunately from our experience, everything is much more difficult and more complicated when you work with human cells. It’s just how it is. But the principal is clear, it will also work in humans, there is no doubt, but it will be harder to try and find out how to do it.
Could this be a cell therapy to those diseases?
PT: I think there are two answers to the question. I think the most tractable set of diseases that currently have no cures, no therapies are the class of very rare genetic disorders called leukodystrophies, this class of disorders where there are specific mutations in the genome. The patients have quite severe symptoms, and most die when they’re quite young.
However, they’re quite rare. So in the context of clinical trials, it’s often challenging to think about having the numbers of patients that would put together good initial safety trials. There’s far more people worldwide with multiple sclerosis. You could design such a trial in a way to safely test the safety of these cells with a high-enough confidence and power to actually know if they were having an impact and remyelinating.
As a NYSCF Investigator, what has the impact of the grant and the community been on your work?
MW: I think NYSCF’s support is wonderful and really enables us to go in these directions. It’s very difficult these days to explore new grounds, to fund a project. In other words, it’s high-risk perhaps but potentially high-reward. So that’s why the NYSCF award for us is really spectacular. We can just go into these areas where we think is the best direction and the most promising. We can do this and these wonderful things can happen that actually works but not always. I think these papers will make quite a splash in the field.
PT: I got this award in my first year when I was starting my faculty position—so I think the biggest aspect for me was the freedom to really test some of the boundaries and some of the really innovative areas of the field. This grant allowed me to pursue the very cutting edge or the innovative areas, “high risk, high reward” aspects that I certainly likely not have pursued without this stable funding source.
I benefited from the meetings and the retreats, interacting with really the best of the best in this particular field and seeing how many of them have charted a path and been very successful and using that information and trying to, as I organize and set up my lab into focus areas moving forward to really provide a successful system to allow us to do some of the things we do in the lab.
It was great seeing both of these papers published in the same journal. It really affirms the power of the Innovator program.
PT: Last year, we both got to the retreat, and Marius and I were sitting on the back bar, and we were just talking. It turned out we were kind of working on the same thing. We probably never would have gotten to where we are now without those interactions. You know “hey, what are you guys doing? This is pretty exciting. How are you doing this?” The NYSCF retreat is really where we discussed this, thought about this, and made a plan for how we were each going to move forward independently but still try to maximize what we’re doing in a really collegial way. Because imagine that it could’ve ended up as really fierce competitors, trying to scoop one another, but throughout this whole process we’ve been very open with each other. I think NYSCF, really, by bringing us together provided us the opportunity to maximize success and get instant replication of this result by these papers being published back-to-back.
What made you want to become a scientist? And work with stem cells?
MW: I’ve always been fascinated by the things around me. As far as I can remember back, it was unbelievable to see all these things and our planet and go why—this really is all a miracle. I ended up studying medicine. When things go slightly wrong—its not much that it takes—it has such a huge impact on the entire organism. We should be able to do something about it. During my PhD time, I sort of was aware there were stem cells. It was right around the time when Dolly the Sheep was cloned, the very first report of the future. I thought, “this is where I have to go.” And that’s what I did! I did my post-doc with Rodolf Jaenisch, who is one of the leading groups certainly in the stem cell field, and stayed with the field since.
PT: Growing up my entire life, I wanted to be a veterinarian. And I went to undergrad here at Case, and I started in the research lab because I was doing pre-vet and, I wanted to have research experience that would allow me to be competitive for some of these programs. As soon as I joined the research lab my freshman year, I became totally fascinated with the ability to ask your own questions and drive the research into completely new areas that no one has ever done before. Looking down a microscope at cells—just the ones we just created—and thinking no one else in the world in the history of time has ever done this before is a pretty rewarding feeling. It gets you up in the morning. And so ever since I joined the lab, I immediately switched: I’m going to do research for the rest of my life. I just knew it immediately. And I really don’t think of it really as work. It’s a really exciting and rewarding feeling.